This research proposal is concerned with the secretion, metabolism, immunological and biological properties of insulin, proinsulin and C-peptide in man. The specific areas of investigation will include: (1) improvements in the methodology for measuring serum proinsulin and C-peptide, (2) characteization of circulating serum proinsulin in families with defects in proinsulin biosynthesis, (3) elucidation of the effect of residual beta cell secretory function in determining clinical control of diabetic subjects, (4) characterization of the abnormal circulating insulin molecule in some diabetic patients, and (5) investigation of the role of circulating insulin antibodies in the syndrome of "autoimmune hypoglycemia".